Emerging trends and hot topics: Presented Tuesday, May 9 at the ARVO Annual Meeting
Anatomy and Pathology/Oncology
#317 - 2741 - A0445. Attention-Related-Functional Changes Induced By Imposed Myopia Defocus from Spectacle Lens. 8:30am.
Myopia is very common, but how it develops is still shrouded in mystery. Increasing evidence from a diverse range of animal studies indicate that eye growth is strongly guided by visual signals, specifically the optical defocus. Could our brain hold the key to explaining this mechanism? Researchers from Beijing Tongren Hospital might have uncovered a clue: They obtained data on cerebral blood flow changes in human brain when they were watching defocus image, and observed that defocus image will enhance the function in 4 specific brain regions. These regions were mostly associated with functions of saccade, attention and awareness (which is crucial to processing visual signals, and can improve sensitivity at perception level), contemplating distance and recognition of image. Their findings revealed that defocus signals could significantly increase attention-related changes in brain regional activity, which suggests a potential direction for future investigation about the relationship between lens-induced myopia and brain. The research shed a light on the role of brain function training and cerebral plasticity in the mechanism of myopia.
#317 - 2744 - A0448. Wavelength Cues Are Essential to Maintain Emmetropia in Tree Shrews. 8:30am.
Nearsightedness is not a genetic disorder. Most children initially develop normal eyesight. This is because the eye actively regulates its growth to achieve and maintain good focus. The problem is that more and more people are developing nearsightedness in childhood and adolescence, and it is not known why.
Nearsightedness is when the eye grows too long to be able to focus. While glasses and contacts and surgery can correct vision, the extra eye growth of nearsightedness also damages the back of the eye. Later in life this can cause severe vision problems including blindness. The epidemic of nearsightedness is a major public health crisis.
We are using tree shrews, small mammals with good vision, closely related to primates, to explore how the eye uses the visual environment to regulate its growth. We have shown that it is not just the sharpness of an image, but also aspects of its color, that are essential for the eyes of a young animal to be able to achieve and maintain good focus. By changing the color of ambient light we can radically increase or decrease the rate of eye growth. These results may open the door to someday preventing nearsightedness.
#334 - 3002. The Presence of Accommodative Tissues Influences the Shape of the Developing Eye. 11:45am.
The cornea, or the transparent layer forming the front of the eye, has a particular curvature that allows the eye to focus. This curvature is significantly different from the white of the eye, though the mechanism by which the eye generates this difference remains elusive. Computational and experimental studies compared the corneal curvature in the presence and absence of adjacent tissues within the eye, indicating that the absence of these tissues results in a cornea which is too flat for good vision. A better understanding of this interplay may allow prevention or treatment of refractive errors such as myopia (near-sightedness) and hyperopia (far-sightedness), as well as diseases related to the cornea and the lens.
#317 - 2747 - A0451. Changes in forward light scatter parameters correlate with refractive error in young adults. 8:30am.
Short-sightedness is strongly correlated with an increase in eye size, particularly eye length. The eye growth can also be linked to adverse changes in the back (posterior) of the eye. It is thought that these changes can negatively impact upon the eye's ability to function.
In our study, we investigated changes to vision caused by the front (anterior) eye and the role of short-sightedness. We found that the anterior eye could play a significant role in reducing visual function in short-sighted eyes. Further work is required to quantify the influence of the anterior eye on visual function.
#334 - 2999. Ocular motor nerve development in the presence and absence of extraocular muscle. 11am.
In certain diseases, children are born unable to fully move their eyes. Each eye is surrounded by six muscles, which work together to move the eye. They are controlled by three nerves, each directing specific muscles. During embryonic development, the nerves grow from the brainstem to the eye muscles. For the eyes to move properly and in concert, each nerve must precisely connect to the proper muscles. To understand disorders of eye movements, it is important to understand how these nerves find their way to the proper muscles. To determine if individual eye muscles secrete cues that attract the proper nerve, we examined genetically modified mice that do not have eye muscles using advanced 3D imaging methods. In these mice, the nerves found their correct places in the orbit, showing that their initial path is not dependent on cues from specific muscles. However, without muscle present to connect to, the nerves failed to branch correctly and did not survive.
#321 - 2909 - B0555. Variation in the use of bevacizumab and ranibizumab for diabetic macular edema. 8:30am.
The advent of anti-vascular endothelial growth factor (VEGF) agents for the treatment of diabetic macular edema (DME) has greatly improved clinical outcomes compared to laser therapy. However, the annual costs of anti-VEGF therapy exceeded $2.3 billion among the fee-for-service (FFS) Medicare population in 2008. Medicare reimbursements were $50 per bevacizumab and $1,903 per ranibizumab injection in 2012. Significant geographic variation in intravitreal anti-VEGF injection rates of bevacizumab and ranibizumab has been reported as well.
We used a 5% sample of 2010-2013 Medicare beneficiaries to investigate distribution of intravitreal bevacizumab and ranibizumab use for DME. Overall, there was a greater frequency of bevacizumab use (86.4%) compared to ranibizumab use (13.6%) for the sample of 5,290 patients with DME. The highest frequencies of bevacizumab use were in the Mountain (92.2%) and West South Central (91.7%) divisions. The highest frequencies of ranibizumab use were in the Mid Atlantic (24.0%) and West North Central (19.9%) divisions. The frequencies of bevacizumab and ranibizumab injections for DME varied significantly between the US census divisions (p<0.0001). Future research into factors driving geographic variation in the use of these agents may help direct cost-effective strategies for the management of DME.
#315 - 2650 - A0240. AUTOMATED NON-INVASIVE METHOD FOR DRY EYE PREDICTION. 8:30am.
Dry eye is a common disease of the tears and ocular surface that affects a large part of the population and it could have a significant and negative impact on people lives. However its diagnosis is not always straightforward and in most cases is invasive. An innovative non-invasive method to diagnose dry eye has been developed. The research is being presented at the 2017 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) this week in Baltimore.
The new method is objective and automated. It is easy to use, enabling clinicians to do a rapid and accurate assessment of the tear film. Results showed that pathological subjects are correctly identified in 91% of the cases. Thus it may be a helpful tool to aid clinicians in diagnosis and monitoring of dry eye.
#322 - 2931 - B0577. A method for rapid objective strabismus angle measurement. 8:30am.
Strabismus, a disease in which the eyes are not parallel, affects about 4% of children, causing double vision and resulting in suppression of one eye's vision and vision deficits, which might become permanent if left untreated. The success of strabismus surgery mainly depends on the accuracy of the eye misalignment measurement. Such measurement is performed nowadays using the same laborious manual method as in the eighteenth century. The child's age, vision, level of cooperation, and the examiner's skill and experience determine the accuracy of this manual measurement. It is also time-consuming and cumbersome, severely limiting children's cooperation.
The presented system is an objective, accurate, rapid automatic measurement method, which is intuitive, simple to use and operable by a technician. The procedure is very simple: the child looks at a dynamic image for less than 30 seconds, a fraction of the time required for conventional manual testing, while the eye-tracking-based method determines the eyes' misalignment.
The efficacy of NovaSight's EyeSwiftâ„¢ system was proven in a clinical study, demonstrating three-fold improvement in result repeatability compared with the conventional measurement. The system can be used for screening, diagnosis and monitoring of strabismus.
#332 - 2991. Longitudinal Changes of Geographic Retinal Darkening in a Cohort of Ebola Survivors. 12:15pm.
The eye provides a unique opportunity to peer inside the human body. With the latest advances in eye imaging technology, we can examine the light detecting cells at the back of the eye in a non-invasive manner of living people in exquisite detail.
Our study involved imaging the back of the eye (the retina) of survivors from the 2014-2016 Ebola epidemic in Sierra Leone over a one year period. All the survivors involved in our study had recovered from their Ebola infection at least one year prior to the study.
Our previous research provided evidence suggesting the virus can enter the eye by travelling along the nerve which connects the eye to the brain. The virus also appears to cause a unique scar on the back of the eye in a proportion of survivors.
We found that many of the Ebola retinal scars were surrounded by areas of darkening which in some cases, extend around the entire retinal periphery. These areas of "˜retinal darkening' represent a structural change in the light processing cells of the eye. They spare the part of the eye responsible for the central vision and therefore survivors are unaware of their existence.
Over the period of our study, we observed the areas of "˜retinal darkening' were not simply a static sign of damage from the previous infection but instead active areas which are constantly evolving. In some survivors, these areas gradually recovered and the light processing cells returned to their normal appearance. However, in others these areas continue to persist and are even expanding in some survivors.
It is unclear if the retinal changes we have observed are a direct effect of the virus within the cells of the eye, a consequence of a healing process or the body's response to areas of previous infection. Whatever the underlying cause maybe, it provides visual evidence of an ongoing process which we believe is a consequence of previous Ebola infection.
Many Ebola survivors have reported ongoing bodily symptoms such as headaches, and joint pains since their infection. Further research is necessary to understand if these eye signs we have identified have any correlation with other symptoms or if these patients are at risk of relapses in the future.
#380 - 3622 - B0181. Binding of HSV-1 UL20 to Golgi-specific Zinc-finger protein affect virus infectivity and latency-reactivation. 3:45pm.
The UL20 protein is an essential gene for HSV-1 infectivity. We have shown that UL20 bind to a cellular protein and this binding is required for HSV-1 infectivity. We also have demonstrated that UL20 protein is modified by this binding and this modification is important for virus infectivity. Mice that lacked this cellular protein had significantly reduced HSV-1 latency and reactivation compared to wild type control mice. Thus, blocking of this interaction, should be considered as a potential therapy for ocular HSV-1 reactivation.
#332 - 2992. Zika Virus Causes Chorioretinal Atrophy in Mouse Eyes and Infects Primary Human Cells Lining the Blood-Retinal Barrier. 12:30pm.
Zika Virus (ZIKV) has emerged as a significant threat to global health and has been increasingly reported to cause disorders in multiple organs, including the eye. Infants born with congenital ZIKV infection had severe ocular abnormalities, primarily in the retina. However, currently it is not known how ZIKV causes lesions in the retina. Here in this study, we investigated the interaction of ZIKV with retinal cells and demonstrated that ZIKV can replicate and survive in multiple retinal cells and ultimately kill them. Next, we tested whether ZIKV can cause retinal damage using an animal model and discovered that ZIKV infection of a mouse eye resulted in retinal lesions referred to as "˜chorioretinal atrophy.' Interestingly, the ZIKV-infected mouse eyes mimicked the features of ZIKV-infected human eye. The major impact of this study is to establish that ZIKV infection can lead to cytopathic and/or immunological damage to the eye. In the wake of rapidly spreading ZIKV and lack of vaccine, this study is of paramount importance to prevent/treat ZIKV complications.
#379 - 3606 - B0165. Prevalence and Diversity of Giant Viruses among Contaminated Contact Lens Cases. 3:45pm.
Giant viruses are a relatively new class of viruses that have been discovered in the environment growing in free living amoeba. The first giant virus was thought to be a bacterium, due to its large size. This virus was name Mimivirus, as it mimicked bacteria in appearance under a microscope. This new class of viruses can carry more genes than some bacteria and has the ability to make its own proteins. This feature raises the question of classifying them as a new class of life. Mimivirus has been isolated from several human samples, including the contact lens case of a patient with a cornea infection, and sputum samples from patients with pneumonia. Our purpose was to screen contact lens cases of patients with cornea infections for the presence of giant viruses and their proteins. We documented the presence of proteins from a variety of giant viruses, including Mimiviridae, Pandoraviridae, Marseilles viruses and Pithoviruses. The role of these viruses in amoeba and ocular infections is still to be determined.
#341 - 3188 - B0219. EGFR signaling promotes TGFÎ²-dependent epithelial-mesenchymal transition (EMT) in the lens. 11am
Scientists have discovered a novel approach to prevent blindness. A leading cause of blindness worldwide is cataract, the clouding of the eye lens. Currently, the only treatment for cataract is surgery that replaces the cloudy lens with an artificial clear lens. In this study, scientists identified a novel compound that prevented the lens cells from developing cataract, thereby maintaining lens transparency. These results are a step closer in the development of a novel drug-based approach for the treatment of cataract.
#383 - 3695 - B0320. Gli1 expression in human epiretinal membranes. 3:45pm.
Epiretinal membrane (ERM) is one of the most common ocular diseases in aged person. Because the cause of the ERM development is not fully elucidated yet, medical treatment is not available for now. The only therapeutic approach is surgical removal, which is expensive and risky. We found that the shh-Gli1 is the key signaling pathway for the development of ERM. We speculate that blocking this signaling pathway would prevent the development and progression of ERM.
#343 - 3218 - B0351. Course of visual field changes in retinitis pigmentosa patients followed by Humphrey Field Analyzer 10-2 program. 11am.
Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by a progressive constriction of the visual field due to photoreceptor degeneration. It affects approximately 1 in 4000 individuals worldwide. The purpose of this study was to determine the progression rate of visual field constriction in 31 RP patients. The results may contribute toward counseling patients, and could be used as a measure in upcoming treatment studies.
#326 - 2949. Continuous submicrogram fluocinolone acetonide (FAc) therapy for the treatment of diabetic retinopathy. 11:45am.
Diabetic macular edema (DME) is a common cause of visual loss among diabetic patients. Most DME pharmacotherapies have a relatively short duration of activity in the eye after administration. The 0.2 ug/day fluocinolone acetonide implant (ILUVIEN) is an FDA-approved therapy for DME designed to deliver a lipophilic corticosteroid for 36 months following a single injection. The benefits to vision in the treatment of DME were established in the phase III FAME clinical trials. Through the current work, we hypothesized that benefits to diabetic retinopathy may also exist due to the continuous therapy for years that the implant delivers. These analyses of the FAME dataset demonstrate significant benefit of this implant in terms of improving diabetic retinopathy severity and protecting the eye from worsening diabetic retinopathy. Importantly, these results were achieved over the three year FAME trial with an average of 1.3 injections. This data adds to the current understanding of the pharmacotherapeutic treatment of diabetic retinopathy and form the basis for future studies. Given that ILUVIEN provides a continuous, multi-year treatment for DME, it has the potential to be a foundation therapy providing constant treatment with the option for occasional shorter acting therapies added during periods of disease exacerbation.
#364 - 3387. Gene Therapy with the Caspase Activation and Recruitment Domain (CARD) Slows the Retina Degeneration of the Sod2 Knock-Out Mouse Model of Geographic Atrophy. 4:15pm.
Age-related macular degeneration (AMD) is a major cause of vision impairment among people 65 years old and above. Even though there is an FDA approved therapy for the "wet" form of AMD, there is not one for the "dry" form of this disease. Current knowledge suggests that dry-AMD is linked to increase oxidation and inflammation within the light sensitive part of the eye known as the retina. Our group design a genetically modified virus that delivers an anti-inflammatory gene to the retina of two mouse models that show increase oxidation within their retina. This virus was injected directly into the eyes of the mice in a procedure similar to those done to deliver approved therapies for wet-AMD. Our virus appeared to be safe, since it did not significantly alter any of the tests that are routinely use to evaluate vision health in humans. In an acute model of oxidative injury, our virus did not block the retinal damage but it allow the recovery of function after one month. In our chronic disease mode, the same virus did not prevent the initial decline in visual function but it stabilized retinal function in older animals as measured by their sensitivity to light.
#383 - 3693 - B0318. Does intravitreal Ocriplasmin degrade intraretinal extracellular matrix molecules? 3:45pm.
Ocriplasmin (OCP) is a drug that is injected into the eye and has been shown to treat a condition known as "Vitreomacular traction", caused by the jelly of the eye pulling on the central retina, the light-sensitive membrane at the back of our eyes.
OCP has been shown to separate the jelly from the retina leading to improved vision. However, side-effects have been demonstrated in some patients through damaging their retina's light-sensitive cells and affecting colour vision. It is thought that this may be due to OCP breaking down molecules in their outer-retinal layers. Thus, we decided to investigate whether this was true.
We studied primate eyes immediately after death and injected some with OCP. We then used a technique called "immunohistochemistry" to identify the presence of specific molecules in the retina.
We could not identify any differences between OCP-injected eyes and those without.
This result could suggest several points: the mechanism described above is not the reason for the side effects observed, or that the OCP concentration was too low to reach the outer-retina. We will repeat the experiments using higher OCP doses and at different injection locations to determine the effect of these clinically important parameters.
#319 - 2800 - B0237. Sub-Tenon's capsule 0.1% adrenaline versus placebo in maintenance of mydriasis during vitrectomy. 8:30am.
Retina is a thin layer of noble cells of the eye that is essential to vision. This fragile structure can be affected by many conditions and sometimes the treatment for retina diseases is a complex surgical procedure called vitrectomy. As the retina is located into the most posterior part of the eye, the pupil must be wide open to allow great visualization. However, sometimes the use of eye drops before surgery can't guarantee this and the pupil starts to close during the surgery, impairing its execution. Our study aimed to find a way to avoid this event by assessing the efficacy of injection under the conjuntival tissue of a drug that could mantain the pupil opened. For this purpose we measured pupil diameters before and after the surgery in two groups, both after received dilation eye drop: one of them received saline solution injection before the surgery and the other received adrenaline 0,1% injection. We concluded, with statistical significance, that adrenaline injection is effective in keeping the pupil opened through the entire eye surgery. We believe that these results may contribute to ophtalmological care by improving the quality of eye surgery.
Retinal Cell Biology
#373 - 3450 - A0073. Analysis of Wnt pathway components during combined intrauterine growth restriction and oxygen-induced retinopathy. 3:45pm.
When infants are born premature, the light sensing part of the eye, i.e., retina, is immature. After birth, premature infants are vulnerable to developing uncontrolled blood vessel growth that leads to retinopathy of prematurity (ROP). Once ROP develops, there is a greater risk of poor vision and blindness. The causes of premature birth are incompletely understood, but one important maternal association is preeclampsia, which affects 4-18% of live births worldwide. It remains unknown if preeclampsia is directly causative or indirectly linked to ROP risk through premature birth. To investigate this, we developed a new model that combines features of maternal preeclampsia with oxygen stresses that increase ROP risk to the offspring.
We implanted a mini-pump that slowly releases an analog of thromboxane A2 into pregnant mice, which causes preeclampsia-like effects. The mouse pups are then placed into a controlled oxygen environment that leads to retinopathy. Surprisingly, pups that survived maternal preeclampsia and were in the oxygen environment grew better and had a tendency to reduced retinopathy compared to pups born to control mothers.
We will use this model in future studies to identify proteins that ultimately may be potentially protective against ROP in premature infants.
#373 - 3451 - A0074. Interleukin 1 Beta reduces hypoxia, prevents neovascularisation and promotes healthy vascular regeneration in oxygen induced retinopathy. 3:45pm.
In conditions such as retinopathy of prematurity, where the blood supply to the retina is insufficient to meet its demand for oxygen, a vascular regenerative response is triggered. This response is exaggerated and results in leaky, abnormal vessels which can go on to cause further blindness in these patients. Using a mouse model that simulates these conditions this study shows that treatment with Interleukin 1 Beta, which is an inflammatory cell signaling protein, can reduce the oxygen demand in retinal tissue where blood supply is insufficient, preventing the formation of abnormal new blood vessels while allowing the healthy regeneration of normal vessels. This novel approach to reducing oxygen demand in poorly vascularised tissue has the potential to be translated into new therapies targeting ischaemic eye conditions such as retinopathy of prematurity.